Process for producing (2R)-2-propyloctanoic acid and intermediate therefor

ABSTRACT

The present invention relates to a process for producing (2R)-2-propyloctanoic acid, which comprises subjecting (2R)-2-hexyloxirane to a two-carbon adding reaction with ring-opening reaction, followed by a protecting reaction of a hydroxyl group to convert it to a compound represented by formula (I): 
                         
(wherein X represents an optionally protected hydroxyl group) and then subjecting the compound to a one-carbon adding reaction to convert it to (2R)-2-propyloctanamide, followed by recrystallization and hydrolysis. According to the process of the present invention, (2R)-2-propyloctanoic acid can be produced by less steps as compared with the conventional method without a dangerous reaction.

TECHNICAL FIELD

The present invention relates to a process for producing(2R)-2-propyloctanoic acid which is useful as a preventive and treatingagent for neurodegenerative diseases caused by dysfunction ofastrocytes, to an intermediate for its production, and to a method forpurifying the same.

BACKGROUND ART

Racemic 2-propyloctanoic acid is known as a preventive and treatingagent for neurodegenerative diseases caused by dysfunction of astrocytes(cf., for example, WO 99/58513). As a result of studies thereafter, ithas been clarified that 2-propyloctanoic acid of an R-form has aparticularly strong activity and, therefore, various investigations havebeen carried out for a process for an efficient production of an R-formsubstance.

With regard to a process for producing (2R)-2-propyloctanoic acid, (1) aprocess in which camphor sultam is used as an asymmetric auxiliarygroup, (2) a process in which L-prolinol is used as an asymmetricauxiliary group, (3) a process in which racemic 2-(2-propynyl)-octanoicacid is reduced after optical resolution (cf EP-A-1078921, JP-A-8-295648and JP-A-8-291106), etc. are known.

With regard to a synthetic method for an optically active 4-alkanolwhich is one of the intermediates used for the production of(2R)-2-propyloctanoic acid, a process in which an optically activealkyloxirane is allowed to react with ethyl magnesium halide isdisclosed (cf JP-A-1-275541).

DISCLOSURE OF THE INVENTION

In the conventional process for producing intermediates for themanufacture of (2R)-2-propyloctanoic acid, there are many steps and adangerous reaction is accompanied therewith and, therefore, it is hardlysaid to be an efficient process for an industrial production of amedicament which is the final product.

Accordingly, an object of the present invention is to provide aproduction process which is suitable for an industrial production bywhich (2R)-2-propyloctanoic acid can be efficiently produced in lesssteps as compared with conventional processes and without a dangerousreaction.

As a result of intensive investigations, the present inventors havesucceeded in the production of (2R)-2-propyloctanoic acid having a highoptical purity (99% ee or more) in three steps from (2R)-2-hexyloxiranevia (2R)-2-proyloctanamide having good crystallinity and excellentpurifying property and thus the present invention has been completed.

Also, (2R)-2-propyloctanamide, (1S)-1-propylheptyl p-toluenesulfonateand (1S)-1-propylheptyl 4-methanesulfonate which are intermediatesuseful in the process for producing (2R)-2-propyloctanoic acid accordingto the present invention are novel compounds.

Thus, the present invention relates to the followings.

-   1. A process for producing (2R)-2-propyloctanoic acid, which    comprises:

subjecting (2R)-2-hexyloxirane to a two-carbon adding reaction withring-opening reaction, followed by a protecting reaction of a hydroxylgroup to convert it to a compound represented by formula (I):

wherein X represents a hydroxyl group which may be protected, and then

subjecting the compound to a one-carbon adding reaction to convert it to(2R)-2-propyloctanamide, followed by recrystallization and hydrolysis.

-   2. A process for producing (2R)-2-propyloctanoic acid, which    comprises hydrolyzing (2R)-2-propyloctanamide.-   3. A process for producing (2R)-2-propyloctanamide, which comprises    subjecting a compound represented by formula (I):

wherein X represents the same meaning as in the above 1,

to a one-carbon adding reaction.

-   4. (2R)-2-Propyloctanamide.-   5. Substantially pure (2R)-2-propyloctanamide.-   6. A compound represented by formula (I):

wherein X represents an optionally protected hydroxyl group.

-   7. The compound according to the above 6, wherein X is    p-toluenesulfonyloxy or methanesulfonyloxy.-   8. A process for producing (2S)-2-propyloctanoic acid, which    comprises hydrolyzing (2S)-2-propyloctanamide.-   9. A process for producing (2S)-2-propyloctanamide, which comprises    subjecting a compound represented by the formula (II):

wherein X represents an optionally protected hydroxyl group,

to a one-carbon adding reaction.

-   10. A process for producing (2S)-2-propyloctanoic acid, which    comprises:

subjecting (2S)-2-hexyloxirane to a two-carbon adding reaction withring-opening reaction, followed by a protective reaction of a hydroxylgroup to convert it to a compound represented by the formula (II), andthen

subjecting the compound to a one-carbon adding reaction to convert it to(2S)-2-propyloctanamide, followed by recrystallization and hydrolysis.

-   11. (2S)-2-Propyloctanamide.-   11. Substantially pure (2S)-propyloctanamide.-   13. A compound represented by the formula (II):

wherein X represents an optionally protected hydroxyl group.

-   14. The compound according to the above 13, wherein X is    p-toluenesulfonyloxy or methanesulfonyloxy.-   15. A process for producing them, and the like.

In the present specification, the “high purity” means that both chemicalpurity and optical purity are high.

In the present specification, the “substantially pure” means that thechemical purity is 95% or more and the optical purity is 95% ee or more.

The “optionally protected hydroxyl group” represented by X in thecompound of formula (I) used in the production process of the presentinvention means a “hydroxyl group which is protected by a removableprotective group”. Examples of the “hydroxyl group which is protected bya removable protective group” include methanesulfonyloxy,p-toluenesulfonyoxy, chloromethanesulfonyloxy,trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy,dimethylphosphonoxy, diethylphosphonoxy, trifluoromethyloxy,benzenesulfonyloxy, naphthalenesulfonyloxy, p-bromobenzenesulfonyloxy,p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy,o-nitrobenzensulfonyloxy and the like. Preferred are methanesulfonyloxy,p-toluenesulfonyloxy, chloromethanesulfonyloxy,trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy andbenzenesulfonyloxy; and more preferred are methanesulfonyloxy andp-toluenesulfonyloxy.

The process of the present invention is carried out according to thefollowing reaction steps (A) to (C). The step (A) is a conversionreaction in which (2R)-2-hexyloxirane is subjected to a two-carbonadding reaction with ring-opening reaction, followed by a protectivereaction of a hydroxyl group to convert it to a compound represented byformula (I); the step (B) is a conversion reaction in which the compoundrepresented by formula (I) is subjected to a one-carbon adding reaction,followed by hydrolysis to convert it to (2R)-2-proyloctanamide; and thestep (C) is a reaction in which (2R)-2-propyloctanamide is hydrolyzed toobtain (2R)-2-propyloctanoic acid.

Hereinafter, each of the steps is explained below in detail.

Step (A):

The conversion reaction of (2R)-2-hexyloxirane to a compound representedby formula (I) is carried out by subjecting (2R)-2-hexyloxirane to atwo-carbon adding reaction with ring-opening reaction, followed by aprotective reaction of a hydroxyl group.

The two-carbon adding reaction with ring-opening reaction is known andis carried out, for example, by reacting (2R)-2-hexyloxirane with anorganic metal reagent having an ethyl group (e.g., ethyl magnesiumchloride, ethyl magnesium bromide, diethyl magnesium, ethyl lithium,ethyl aluminum dichloride, diethyl aluminum chloride, triethyl aluminum,ethyl trimethyl silane, triethyl manganese lithium, ethyl zinc chloride,diethyl zinc, tetraethyl tin, triethyl tin chloride, triethyl tinbromide, diethyl tin dichloride, diethyl tin dibromide, ethyl tintrichloride, triethyl borane, a reagent wherein they are mixed with thefollowing metal catalyst in any ratio, etc.) at −78 to 20° C. in anorganic solvent (e.g., tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, diethyl ether, cyclopentyl methyl ether, 2-methoxy ethylether, benzene, toluene, dimethoxyethane, hexane, heptane, cyclohexane,dichloromethane, chloroform, dichloroethane, hexamethyl phosphoramide,dimethylimidazolidinone, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, dimethyl sulfoxide,1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, a mixed solvent of twoor more thereof in any ratio, etc.) in the presence or absence of ametal catalyst (e.g., copper cyanide, copper chloride, copper iodide,copper bromide, lithium chloride, boron trifluoride. diethyl ethercomplex, titanium chloride, etc.).

The protective reaction of a hydroxyl group is known and it is carriedout, for example, at −78 to 50° C. by adding a sulfonyl chloride (e.g.,methanesulfonyl chloride, p-toluenesulfonyl chloride,chloromethanesulfonyl chloride, trichloromethanesulfonyl chloride,trifluoromethanesulfonyl chloride, benzenesulfonyl chloride,naphthalenesulfonyl chloride, p-bromobenzenesulfonyl chloride,p-nitrobenzenesulfonyl chloride, m-nitrobenzenesulfonyl chloride,o-nitrobenzenesulfonyl chloride, etc.), a phosphoryl chloride (e.g.,diphenylphosphoryl chloride, diethylphosphoryl chloride, etc.) or anacid anhydride (e.g., trifluoroacetic acid, anhydride, etc.), using anorganic solvent (e.g., tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, diethyl ether, cyclopentyl methyl ether, 2-methoxy ethylether, benzene, toluene, dimethoxyethane, hexane, heptane, cyclohexane,dichloromethan, chloroform, dichloroethane, hexamethylphosphoramide,dimethylimidazolidinone, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, dimethyl sulfoxide,1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, a mixed solvent thereofin any ratio, etc.) or in the absence of a solvent, in the presence orabsence of a base [alkylamine (e.g., triethylamine,diisopropylethylamine, tributylamine, etc.), aromatic amine (e.g.,N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, lutidine,collidine, etc.) or a mixture of those amines, or alkali metal hydride(e.g., sodium hydride, potassium hydride, etc.)].

The step (A) in which (2R)-2-hexyloxirane is subjected to a two-carbonadding reaction with ring-opening reaction, followed by a protectivereaction of a hydroxyl group to convert it to a compound represented byformula (I) may be carried out either by a single step (one pot) inwhich (4S)-decan-4-ol produced as an intermediate is not isolated but ahydroxyl group is subjected to a protective reaction in a reactionsystem, or by two steps in which the intermediate is isolated and thenthe hydroxyl group is subjected to a protective reaction. The conversionreaction is preferably carried out by a single step (one pot).

In the process in which the step (A) is carried out by one pot,(2R)-2-hexyloxirane is subjected to a two-carbon adding reaction withring-opening reaction and then the resulting (4S)-decan-4-ol issubjected to a protective reaction of a hydroxyl group withoutisolation. Thus, (2R)-2-hexyloxirane is allowed to react with an organicmetal reagent having an ethyl group in an organic solvent at −78 to 20°C. in the presence or absence of a metal catalyst, and then theprotective reaction of a hydroxyl group is carried out in this reactionsystem. The protective reaction of a hydroxyl group is carried out at−78 to 50° C. by adding sulfonyl chloride, phosphoryl chloride or acidanhydride to the reaction mixture in the presence or absence of a base.

In a converting reaction of (2R)-2-hexyloxirane to (4S)-decan-4-ol by atwo-carbon adding reaction with ring-opening reaction in the step (A),it is preferred to use tetrahydrofuran as an organic solvent. It is alsopreferred to use ethyl magnesium chloride as an organic metal reagenttogether with copper chloride which is a metal catalyst.

The compound represented by formula (I) is preferably(1S)-1-propylheptyl p-toluenesulfonate or (1S)-1-propylheptylmethanesulfonate.

In a converting reaction from (4S)-decan-4-ol to (1S)-1-propylheptylp-toluenesulfonate which is formula (I) wherein X isp-toluenesulfonyloxy in the step (A), it is preferred that no organicsolvent is used (without a solvent), p-toluenesulfonyl chloride is usedas a sulfonyl chloride, and pyridine is used as a base.

In a converting reaction from (4S)-decan-4-ol to (1S)-1-propylheptylmethanesulfonate which is formula (I) wherein X is methanesulfonyloxy inthe step (A), it is preferred that tetrahydrofuran is used as an organicsolvent, methanesulfonyl chloride is used as a sulfonyl chloride, andtriethylamine and 4-dimethylaminopyridine are used in combination as abase.

Step (B):

The conversion reaction from a compound represented by formula (I)prepared in the step (A) to (2R)-2-propyloctanamide is carried out bysubjecting the compound represented by formula (I) to a one-carbonadding reaction, followed by hydrolysis.

As the one-carbon adding reaction, a cyanidation reaction isexemplified. The cyanidation reaction is known and is carried out, forexample, by reacting the compound at 20 to 80° C. with a cyanidationreagent (e.g., potassium cyanide, sodium cyanide, lithium cyanide,calcium cyanide, trimethylsilyl cyanide, diethyl aluminum cyanide,t-butyl cyanide, acetone cyanohydrin, etc.) in an organic solvent (e.g.,tetrahydrofuran, 2-methoxy ethyl ether, dimethoxyethane, acetonitrile,1,4-dioxane, acetone, hexamethylphosphoramide, dimethylimidazolidinone,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,dimethyl sulfoxide, 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, amixed solvent thereof in any ratio, etc.).

The hydrolysis reaction is also known and is carried out, for example,by reacting the compound at 0 to 50° C. with a peracid (e.g., hydrogenperoxide, t-butyl hydroperoxide, perbenzoic acid, m-chloroperbenzoicacid, an aqueous solution thereof, etc.) in an organic solvent (e.g.,tetrahydrofuran, 2-methoxy ethyl ether, dimethoxyethane, acetonitrile,1,4-dioxane, acetone, hexamethylphosphoramide, dimethylimidazolidinone,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,dimethyl sulfoxide, 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, amixed solvent thereof in any ratio, etc.) or without a solvent.

The reaction shown by the step (B) in which the compound represented byformula (I) is subjected to a one-carbon adding reaction to give(2R)-2-propyloctanenitrile, followed by hydrolysis to convert it to(2R)-2-propylheptanamide may be carried out in one step (one pot) inwhich (2R)-2-propyloctanenitrile produced as an intermediate is notisolated but subjected to hydrolysis reaction in a reaction system, ormay be carried out in two steps in which the intermediate is isolatedand then subjected to hydrolysis reaction. The one step (one pot) methodis preferred.

In the process in which the step (B) is carried out by one pot, thecompound represented by formula (I) is subjected to a cyanidationreaction, and then the resulting (2R)-2-propyloctanenitrile ishydrolyzed without isolation. Thus, the compound represented by formula(I) is allowed to react with a cyanidation reagent in an organic solventat 20 to 80° C., and then the hydrolysis reaction is carried out at thetemperature of 0 to 50° C. by adding a peracid to the reaction system.

In a cyanidation reaction in the step (B) in which (1S)-1-propylheptylp-toluenesulfonate is subjected to a one-carbon adding reaction toconvert it to (2R)-2-propyloctanenitirle, it is preferred to usedimethyl sulfoxide as an organic solvent and sodium cyanide as acyanidation reagent.

In a cyanidation reaction in the step (B) in which (1S)-1-propylheptylmethanesulfonate is subjected to a one-carbon-increasing reaction toconvert it to (2R)-2-propyloctanenitrile, it is preferred to usedimethyl sulfoxide as an organic solvent and lithium cyanide as acyanidation reagent.

In a reaction in the step (B) in which (2R)-2-propyloctanenitrile ishydrolyzed to convert it to (2R)-2-propyloctanamide, it is preferred touse dimethyl sulfoxide as an organic solvent and a 30% hydrogen peroxidesolution as a peracid.

In order to obtain (2R)-2-propyloctanamide of high purity in theconversion reaction in the step (B), purification can be carried out byrecrystallization, if necessary. Examples of the solvent forrecrystallization include water, ethanol, methanol, n-propanol,isopropanol, n-butanol, acetonitrile, acetone, dimethoxyethane,tetrahydrofuran, ethyl acetate, isopropyl acetate, toluene, n-heptane,diethyl carbonate, t-butyl methyl ether, acetic acid, a mixed solvent oftwo or more of those solvents in any ratio, and the like. Preferred is amixed solvent of water and acetonitrile.

Step (C):

The converting reaction from (2R)-2-propyloctanamide to(2R)-2-propyloctanoic acid is carried out by subjecting(2R)-2-propyloctanamide to a hydrolyzing reaction. The hydrolyzingreaction is known and carried out, for example, by reaction at 20 to160° C. using an acid [inorganic acid (e.g., hydrochloric acid, sulfuricacid, hydrobromic acid, nitric acid, phosphoric acid, a mixture thereof,etc.), organic acid (e.g., formic acid, acetic acid, propionic acid,trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid,trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, camphorsulfonic acid, oxalic acid, citric acid, a mixture thereof,etc.) or a mixture thereof, an aqueous solution thereof, etc.].

In a converting reaction of (2R)-2-propyloctanamide by hydrolysis to(2R)-2-propyloctanoic acid in the step (C), it is preferred to use amixture of 6 mol/L hydrochloric acid and acetic acid, as an acid.

Additionally, it is also possible in the above reaction steps that, forexample, in the step (A), a two-carbon adding reaction is carried outusing an unsaturated organic metal reagent (e.g., vinyl magnesiumchloride, vinyl magnesium bromide, ethynyl magnesium chloride, ethynylmagnesium bromide, etc.) as an organic metal reagent, the resulting(4R)-1-decen-4-ol or (4R)-1-decyn-4-ol is subjected to the reactions ofthe step (B) or the step (C), and the resulting(2R)-(2-propenyl)octanoic acid or (2R)-(2-propynyl)octanoic acid isreduced by the method mentioned in WO 99/58513 and WO 00/48982 to give(2R)-2-propyloctanoic acid of high purity.

Furthermore, as is apparent for the person skilled in the art, it isalso possible in the present invention to produce (2S)-2-propyloctanoicacid of high purity using (2S)-2-hexyloxirane as a starting materialinstead of (2R)-2-hexyloxirane.

The intermediates and products prepared by the present invention can beisolated and purified by a known isolating and purifying means such asconcentration, concentration in vacuo, distillation, distillation invacuo, extraction with a solvent, crystallization, recrystallization,transfer into solvent and chromatography.

In the present invention, unless otherwise indicated, as is easilyunderstood by the person skilled in the art, the symbol

 indicates that the substituent attached thereto is behind the sheet(i.e., α-position), the symbol

 indicates that the substituent attached thereto is in front of thesheet (i.e., β-position), the symbol

 indicates that it is α-position, β-position or a mixture thereof in anyratio, and the symbol

 indicates that it is a mixture of α-position and β-position in anyratio.

EFFECTS OF THE INVENTION

The present invention provides a process for producing(2R)-2-propyloctanoic acid having high optical purity which is useful asa preventive and/or treating drug for neurodegenerative diseases causedby dysfunction of astrocytes starting from (2R)-2-hexyloxirane byhydrolysis via crystalline (2R)-2-propyloctanamide. The process of thepresent invention is a method suitable for industrial production inwhich (2R)-2-propyloctanoic acid can be prepared by less steps ascompared with the conventional method without a dangerous reaction.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will now be illustrated in detail by way of thefollowing Examples although the present invention is not limitedthereto. Solvents for the measurement of NMR in the following Examplesare heavy chloroform in all cases.

Solvents in the passage for separation by chromatography and inparentheses for TLC are an eluting solvent or a developing solvent usedtherefor and the rate is ratio by volume.

EXAMPLE 1 Production of (1S)-1-propylheptyl p-toluenesulfonate:

(2R)-2-Hexyloxirane (1.22 mL, 100% ee) was added dropwise to atetrahydrofuran (2.21 mL) solution of copper chloride (15.8 mg) at −20°C. under argon atmosphere, and then a 2.11 mol/L ethyl magnesiumchloride in tetrahydrofuran solution (4.55 mL) was added dropwisethereto. The reaction mixture was stirred at −20° C. for 1.5 hours, anda tetrahydrofuran solution of p-toluenesulfonyl chloride (1.83 g) wasadded dropwise thereto, followed by stirring for 1.5 hours. Then, thetemperature was raised up to 0° C., followed by stirring for 3.5 hours.To the reaction solution were added water and pyridine, followed bystirring at 0° C. for 40 minutes, ethyl acetate was added thereto andthe mixture was successively washed with 10% sulfuric acid (twice),water and brine and concentrated to give the title compound (2.27 g)having the following physical data.

TLC: Rf 0.30 (hexane:ethyl acetate=10:1); NMR: δ 0.82-0.87 (m, 6H),1.10-1.35 (m, 10H), 1.49-1.64 (m, 4H), 2.44 (s, 3H), 4.57 (m, 1H), 7.32(d, 2H, J=8.4 Hz), 7.79 (d, 2H, J=8.4 Hz).

EXAMPLE 2 Production of (2R)-2-propyloctanamide:

Sodium cyanide (470 mg) was added to a dimethyl sulfoxide (9.6 mL)solution of the compound prepared in Example 1(1.5 g) under argonatmosphere, followed by stirring at 40° C. for 10 hours. The reactionmixture was cooled in a water bath, a 35% hydrogen peroxide solution(0.42 mL) was added dropwise thereto, and potassium carbonate (78.8 mg)was added thereto, followed by stirring at 40° C. 35% hydrogen peroxidesolution (0.42 mL) was further added twice dropwise thereto after 1.5hours and 6 hours after the start of the stirring at 40° C. Then, asaturated sodium sulfite solution and water were added thereto at 0° C.to precipitate crystals. The crystals were filtered and washed withwater and a mixed solvent of acetonitrile and water (1:1) in this orderto give the title compound (352 mg).

TLC: Rf 0.24 (hexane:ethyl acetate=1:1); NMR: δ 0.84-0.94 (m, 6H),1.26-1.64 (m, 14H), 2.04-2.15 (m, 1H), 5.42 (bs, 1H), 5.59 (bs, 1H);Optical purity: 99.5% ee (confirmed by HPLC, from (2R)-2-hexyloxylane).

EXAMPLE 3 Production of (2R)-2-propyloctanenitrile:

Sodium cyanide (688 mg) was added to a dimethyl sulfoxide (14 mL)solution of the compound prepared in Example 1 (2.44 g, prepared by 100%ee (4S)-decan-4-ol) under argon atmosphere, followed by stirring at 40°C. for 10 hours.

To the reaction solution was added a mixed solvent of heptane and ethylacetate (1:9), the mixture was successively washed with water and brineand concentrated and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=50:1) to give the title compound(815 mg) having the following physical data.

TLC: Rf 0.54 (hexane:ethyl acetate=10:1); NMR: δ 0.89 (t, 3H, J=6.8 Hz),0.96 (t, 3H) J=7.0 Hz), 1.12-1.70 (m, 14H), 2.50 (m, 1H); Opticalpurity: 98.5% ee (confirmed by HPLC).

EXAMPLE 4 Production of (2R)-2-propyloctanamide:

A dimethyl sulfoxide (1.95 mL) solution of the compound prepared inExample 3 (156 mg, 98.5% ee) was cooled in a water bath, a 35% hydrogenperoxide solution (0.23 mL) was added dropwise thereto, and thenpotassium carbonate (25.7 mg) was added thereto. The reaction mixturewas stirred at 40° C. for 3 hours and a saturated aqueous solution ofsodium sulfite (1 mL) and water (2 mL) were added thereto at 0° C. toprecipitate crystals. The crystals were filtered and washed with heptaneand water to give the title compound (172 mg).

Optical purity: 98.9% ee (confirmed by HPLC).

EXAMPLE 5 Recrystallization of (2R)-2-propyloctanamide:

The compound prepared in Example 4 (500 mg) having optical purity of96.0% ee was dissolved in acetonitrile (4.5 mL) and water (5.5 mL) byheating and allowed to cool and crystals precipitated were filtered. Thecrystals were washed with water to give the title compound (430 mg).

Optical purity: 99.5% ee (confirmed by HPLC).

EXAMPLE 6 Production of (2R)-2-propyloctanoic acid

Acetic acid (0.35 mL) and 6 mol/L hydrochloric acid (0.35 mL) were addedto the compound prepared in Example 2 or 5 (70 mg, 99.5% ee), followedby stirring at 130° C. for 10 hours. The reaction mixture was allowed tocool, heptane was added thereto and the mixture was washed with a brineand concentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1) to give the title compound(52.4 mg) having the following physical data.

TLC: Rf 0.54 (hexane:ethyl acetate=7:3); NMR: δ 0.86-0.93 (m, 6H),1.25-1.50(m, 12H), 1.57-1.67 (m, 2H), 2.36 (m, 1H); Optical purity:99.2% ee (derived to phenacyl ester, followed by confirmation of opticalpurity by HPLC).

EXAMPLE 7 Production of (2S)-2-propyloctanoic acid

The same operations as in Example 1→Example 2→Example 6 were carried outusing (2S)-2-hexyloxirane instead of (2R)-2-hexyloxirane to give thecompound of the present invention having the following physical data.

TLC: Rf 0.54 (hexane:ethyl acetate=7:3); NMR: δ 0.86-0.93 (m, 6H),1.25-1.50 (m, 12H), 1.57-1.67 (m, 2H), 2.36 (m, 1H); Optical rotation:[α]_(D)+5.19 (c=2.70, chloroform).

INDUSTRIAL APPLICABILITY

The present invention provides a process for producing(2R)-2-propyloctanoic acid in high optical purity which is useful as apreventive and/or treating drug for neurodegenerative diseases caused bydysfunction of astrocytes starting from (2R)-2-hexyloxirane byhydrolysis via crystalline (2R)-2-propyloctanamide. The process of thepresent invention is a method suitable for industrial production inwhich (2R)-2-propyloctanoic acid is able to be prepared by less steps ascompared with the conventional method without a dangerous reaction.

1. A process for producing (2R)-2-propyloctanoic acid, which comprises:subjecting (2R)-2-hexyloxirane to a two-carbon adding reaction withring-opening reaction, followed by a reaction to protect the hydroxylgroup with a removable protective group by reacting the hydroxyl groupwith a sulfonyl chloride, a phosphoryl chloride or an acid anhydride toobtain a compound represented by formula (I):

wherein X represents a hydroxyl group which is protected by a removableprotective group, and then subjecting the compound to a one-carbonadding reaction to obtain (2R)-2-propyloctanamide, followed byrecrystallization and hydrolysis.
 2. A process for producing(2R)-2-propyloctanoic acid, which comprises hydrolyzing isolated(2R)-2-propyloctanamide.
 3. A process for producing(2R)-2-propyloctanamide, which comprises subjecting a compoundrepresented by formula (I):

wherein X represents a hydroxyl group which is protected by a removableprotective group, to a one-carbon adding reaction.